Project Summary/Abstract. Each year, millions of children in the United States have surgery under anesthesia. Recent population studies have suggested that children who undergo multiple exposures to anesthesia and surgery at an earlier age could have an increased risk for developing neurocognitive impairment. It is therefore urgent to perform studies in this new and still under-investigated area: anesthesia/surgery-associated neurocognitive impairment in children. Thus far, no biomarker for identifying neurocognitive impairment currently exists and this gap in knowledge impedes the progress of the research. To address this issue, we have made a proposal to establish the biomarker for anesthesia/surgery-associated neurocognitive impairment in children. Consistent with the notion that Tau protein is a marker of brain injury in infants and children with hypoxic ischemic encephalopathy and hydrocephalus, our preliminary studies showed that multiple exposures to the anesthetic sevoflurane increased blood Tau levels and induced neurocognitive impairment in young mice. Thus, the hypothesis of the proposed study is that children have elevated Tau and phosphorylated Tau levels and develop neurocognitive impairment after multiple, but not single, surgeries under anesthesia. We will test this hypothesis in two cohorts of children between 3 and 5 year-old: (1) 20 children undergoing reconstruction surgery to repair burn scars who will likely develop the neurocognitive impairment due to the histories of multiple exposures to anesthesia/surgery used to treat the burn; and (2) 20 children having hernia repair surgery for the first time who will likely NOT develop the neurocognitive impairment due to a lack of history of exposure to anesthesia/surgery. In Aim 1, we will use the NIH Toolbox and innovative nanobeam technology to determine neurocognitive outcomes as well as blood Tau and phosphorylated Tau levels before and after the anesthesia/surgery. We will also collect information of eligible:recruit ratio, retention rates, protocol safety, and power calculation. In Aim 2, we will measure Tau and phosphorylated Tau in urine, feces and saliva of 10 participants recruited in Aim 1. Taken together, these high risk but high impact prospective cohort studies in children would provide important information for the application of the R01 grant to further establish Tau or phosphorylated Tau as the biomarker of the anesthesia/surgery-associated neurocognitive impairment in children. The establishment of the biomarker will help diagnose the anesthesia/surgery-associated neurocognitive impairment, identify neurotoxic anesthetics, and determine the outcomes of intervention(s). These research works will ultimately lead to safer anesthesia/surgery care and better postoperative outcomes for children. Therefore, these efforts are consistent with the goal of the funding opportunity announcement PAR-18-214: to improve the safety and effectiveness of current drugs for pediatric or obstetric patients.